Integrated Metabolomics and Lipidomics Analysis Reveal Remodeling of Lipid Metabolism and Amino Acid Metabolism in Glucagon Receptor-Deficient Zebrafish.
Integrated Metabolomics and Lipidomics Analysis Reveal Remodeling of Lipid Metabolism and Amino Acid Metabolism in Glucagon Receptor-Deficient Zebrafish.
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综合代谢组学和脂质组学分析揭示胰高血糖素受体缺陷斑马鱼氨基酸代谢和脂质代谢的重塑
DOI：
10.3389/fcell.2020.605979
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发表时间：
2020
影响因子：
5.5
通讯作者：
Li M
中科院分区：
文献类型：
--
作者：
Bai X;Jia J;Kang Q;Fu Y;Zhou Y;Zhong Y;Zhang C;Li M
胰高血糖素受体（GCGR）由胰高血糖素激活，对动物的葡萄糖、氨基酸和脂质代谢至关重要。GCGR阻断已被证明可诱导生物体中的低血糖、高氨基酸血症、高胰高血糖素血症、肥胖减少、脂肪肝和胰腺α细胞增生。然而，GCGR如何调节这些生理功能的机制还不是很清楚。在我们之前的研究中，我们使用GCGR突变体斑马鱼（gcgr−/−）通过RNA-seq揭示了GCGR在转录水平上调节代谢网络。在这里，我们进一步对野生型和gcgr−/−斑马鱼进行了全生物代谢组学和脂质组学分析，以研究代谢物的变化。我们从代谢组学分析中发现了107种显著不同的代谢物，从脂质组学分析中发现了87种显著不同的脂质。结合转录组学数据的化学物质分类和途径分析均揭示了gcgr缺陷斑马鱼的氨基酸代谢和脂质代谢发生了重构。与其他研究类似，我们的研究表明，gcgr−/−斑马鱼表现出尿素生成减少和胆固醇代谢受损。更有趣的是，我们发现在gcgr−/−斑马鱼中甘油磷脂代谢被破坏，花生四烯酸代谢被上调，色氨酸代谢途径被下调。基于组学数据，我们进一步验证了我们的发现，揭示了gcgr−/−斑马鱼表现出抑制褪黑激素昼夜节律和增加运动活动。这些全局组学数据使我们更好地理解GCGR在调节代谢网络中的作用，并对GCGR的生理功能有了新的认识。
The glucagon receptor (GCGR) is activated by glucagon and is essential for glucose, amino acid, and lipid metabolism of animals. GCGR blockade has been demonstrated to induce hypoglycemia, hyperaminoacidemia, hyperglucagonemia, decreased adiposity, hepatosteatosis, and pancreatic α cells hyperplasia in organisms. However, the mechanism of how GCGR regulates these physiological functions is not yet very clear. In our previous study, we revealed that GCGR regulated metabolic network at transcriptional level by RNA-seq using GCGR mutant zebrafish (gcgr−/−). Here, we further performed whole-organism metabolomics and lipidomics profiling on wild-type and gcgr−/− zebrafish to study the changes of metabolites. We found 107 significantly different metabolites from metabolomics analysis and 87 significantly different lipids from lipidomics analysis. Chemical substance classification and pathway analysis integrated with transcriptomics data both revealed that amino acid metabolism and lipid metabolism were remodeled in gcgr-deficient zebrafish. Similar to other studies, our study showed that gcgr−/− zebrafish exhibited decreased ureagenesis and impaired cholesterol metabolism. More interestingly, we found that the glycerophospholipid metabolism was disrupted, the arachidonic acid metabolism was up-regulated, and the tryptophan metabolism pathway was down-regulated in gcgr−/− zebrafish. Based on the omics data, we further validated our findings by revealing that gcgr−/− zebrafish exhibited dampened melatonin diel rhythmicity and increased locomotor activity. These global omics data provide us a better understanding about the role of GCGR in regulating metabolic network and new insight into GCGR physiological functions.